Sistema modulatório descendente da dor na fibromialgia : preditores de disfunção e conectividade funcional por ressonância magnética funcional

A fibromialgia (FM) é uma síndrome que se caracteriza por dor musculoesquelética generalizada, fadiga, sono não reparador, alterações cognitivas, sintomas depressivos e neurovegetativos, cujo processo neurobiológico é múltiplo e complexo. Apesar de ser de grande relevância ao indivíduo e à sociedade, esta patologia com frequência não recebe a atenção necessária pelos órgãos que definem as prioridades da assistência na saúde. A prevalência populacional, segundo os critérios da Sociedade Americana de Reumatologia, chega a 5,4%, e os gastos decorrentes de atendimento, impostos e aposentadoria precoce por incapacidade são estimados em mais de 29 bilhões de dólares ao ano nos EUA. A falha das terapêuticas farmacológicas convencionais ocorre em cerca de 50% dos pacientes. Postula-se que essas taxas elevadas de insucesso se devam em parte à falta de conhecimento sobre os mecanismos fisiopatológicos. O mecanismo que permeia o conjunto de sintomas que constituem a FM é a síndrome de sensibilização central (SSC). O conjunto de sintomas inclui o sofrimento psíquico, distúrbios do sono, fadiga, dor, alodínia e hiperalgesia. Esta condição tem como mecanismo fisiopatológico o funcionamento prejudicado de neurônios e circuitos em vias nociceptivas, com aumento do campo receptivo, da eficácia sináptica da excitabilidade e redução da inibição. Outro componente fundamental na SSC é a disfunção do sistema modulatório descendente da dor (SMDD), que pode ser avaliado através do teste de modulação condicionada da dor (conditioned pain modulation test [CPM-test]). Neste teste, os participantes podem ser classificados como respondedores ou não respondedores, sendo que neste último grupo há uma perda da capacidade de inibição do SMDD. Estudos de neuroimagem em pacientes com dor crônica demonstram alterações funcionais corticais e de suas conexões com estruturas subcorticais que constituem a neuromatriz da dor. Entre as técnicas de neuroimagem, merece destaque o estudo com ressonância magnética funcional (fMRI) em estado de repouso (do inglês, resting-state [fMRI ou rs-fMRI]), para avaliar a conectividade funcional intrínseca (CFI). Com a finalidade de compreender fatores clínicos, laboratoriais e de neuroimagem que poderiam discriminar a disfunção do SMDD, foram desenvolvidos dois estudos. No primeiro estudo, buscamos identificar se um conjunto de sintomas da FM e os biomarcadores de neuroplasticidade poderiam constituir um índice composto de gravidade, bem como se esse teria poder discriminatório para identificar respondedores e não respondedores ao teste de CPM. Nesse estudo transversal foram incluídas 117 mulheres com FM (n = 60) não respondedoras e (n = 57) respondedoras, com idade entre 30 e 65 anos. A avaliação do SMDD pelo teste de CPM foi feita pelas mudanças nos escores da escala numérica de dor, usando-se um protocolo padronizado. A análise de regressão logística multivariada hierárquica foi usada para construir um índice ajustado ao escore de propensão para identificar não respondedores em comparação com respondedores ao teste de CPM. As seguintes variáveis foram mantidas nos modelos: uso de analgésico quatro ou mais vezes por semana, limiar de dor ao calor (heat pain threshold, HPT), má qualidade do sono, catastrofização da dor, níveis séricos de fator neurotrófico derivado do cérebro (BDNF), número de diagnósticos psiquiátricos e impacto dos sintomas da FM na qualidade da vida. A receiver operating characteristic curve (ROC) mostrou que os não respondedores podem ser discriminados dos respondedores por um índice composto pelos sintomas da FM combinados a marcadores de neuroplasticidade (área sob a curva [AUC] = 0,83; sensibilidade = 100%; especificidade = 98%). O segundo estudo avaliou padrões de CFI entre as redes cerebrais de processamento da dor e o SMDD, através da rs-fMRI em pacientes com FM. Além disso, investigamos se o padrão de conectividade entre o córtex somatossensorial primário (do inglês, primary somatosensory córtex [PSC ou S1]) e a substância cinzenta periaquedutal (do inglês, periaqueductal gray matter [PAG]) está relacionado aos sintomas clínicos, em pacientes respondedoras e não respondedoras ao CPMtest. Nesse estudo, foram incluídas 33 mulheres com FM, classificadas como não respondedoras (n = 13) e respondedores (n = 20) ao teste de CPM. Na análise em que comparamos respondedoras e não respondedoras com um modelo linear generalizado, identificamos que não respondedoras apresentaram diminuição da CFI entre o PSC e a PAG (χ2 =10,41; DF = 1; p < 0,001). A CFI S1-PAG no hemisfério cerebral esquerdo foi positivamente correlacionada aos níveis de sintomas de sensibilização central e negativamente correlacionada à qualidade do sono e aos escores de dor. A análise com ROC mostrou que a CFI entre o S1-PAG oferece sensibilidade e especificidade de 85% ou mais (AUC 0,78; IC 95% 0,63-0,94) para discriminar respondedoras de não respondedoras ao CPM-test. Os achados desses estudos mostram que os sintomas cardinais da FM e marcadores de neuroplasticidade predizem a disfunção do SMDD, assim como os padrões de CFI em estado de repouso no S1-PAG podem ser potenciais marcadores para predizer a resposta à tarefa da CPM. Esses dados podem auxiliar na identificação de perfis para o planejamento individualizado do tratamento de pacientes com fibromialgia.Fibromyalgia (FM) is a syndrome characterized by generalized musculoskeletal pain, fatigue, non-repairing sleep, cognitive, and neurovegetative changes, with multiple and complex neurobiological processes. Despite being a significant disease, it often does not receive attention from the organs that define health care policies. The population prevalence, according to the criteria of the American Society of Rheumatology, reaches 5.4%, and the expenses arising from care, taxes and disability anticipation are estimated at more than 29 billion dollars per year in the US. Failure of pharmacological therapies occurs in about 50% of patients. These high failure rates are postulated partly due to a lack of knowledge about the pathophysiological mechanisms. The mechanism that permeates the set of symptoms that configure FM is the central sensitization syndrome (CSS), which is characterized by distress, sleep disturbances, fatigue, pain, allodynia, and hyperalgesia. This condition has as pathophysiological mechanism the impaired nociceptive functioning of neurons and circuits, increasing the receptive field and reduction of excitation mechanisms. Another critical factor in CCS is the dysfunction of the descending pain modulatory system (DPMS), which can be assessed using the conditioned pain modulation test (CPM test). This test can classify participants as responders and nonresponders, where in this last group, t mechanism of pain inhibition is dysfunctional. Neuroimaging studies have shown there are changes in the brain connectivity in FM patients, mainly among the pain neuromatrix and in the DPMS. Among the neuroimaging techniques, the functional magnetic resonance imaging (fMRI) in resting-state (rs-fMRI) stands out in assessing intrinsic connectivity (IFC). In order to understand clinical, laboratory and neuroimaging factors that could discriminate SMDD dysfunction, two studies were developed. In the first study, we sought to identify whether a set of FM symptoms and neuroplasticity biomarkers could constitute a composite severity index and whether it would have discriminatory power to identify responders and non-responders to the CPM test. In this crosssectional study, 117 women with FM (n = 60) non-responders and (n = 57) responders, aged between 30 and 65 years, were included. Assessment of DPMS by the CPM test was assessed by changes in Numerical Pain Scale (NPS-10) scores using a standardized protocol. Hierarchical multivariate logistic regression analysis was used to construct a propensity scoreadjusted index to identify non-responders compared with CPM test responders. The models maintained the following variables: analgesic use four or more times a week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum BDNF levels, number of psychiatric diagnoses and the impact of FM symptoms on quality of life. The receiver operating characteristic curve (ROC) showed that non-responders could be distinguished from responders by an index composed of FM symptoms combined with neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity). = 98%). The second study evaluated IFC patterns between brain pain processing networks and DPMS using rs-fMRI in FM patients. In addition, we investigated whether the connectivity pattern between the primary somatosensory cortex and the periaqueductal gray is related to clinical symptoms in CPM-test responders or non-responders. In this study, 33 women with FM were classified as nonresponders (n=13) or responders (n=20) to the CPM test. In the analysis that compared responders and non-responders with a generalized linear model (GLM), we identified that nonresponders showed a decrease in IFC between the PSC and the PAG [(χ2 =10.41, DF = 1 p < 0.001)]. IFC S1-PAG in the left cerebral hemisphere was positively correlated with levels of central sensitization symptoms and negatively correlated with sleep quality and pain scores. ROC analysis showed that the IFC between S1-PAG offers sensitivity and specificity of 85% or greater [AUC 0.78, 95% confidence interval (CI), 0.63-0.94] to discriminate responders from non-responders. Respondents to the CPM test. Findings from these studies show that cardinal symptoms of FM and neuroplasticity markers predict DPMS dysfunction and resting-state IFC patterns in S1-PAG may be potential markers for predicting CPM task response. These data can help identify profiles for individualized treatment planning for patients with fibromyalgia

Primary pancreatic sarcoma

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Primary Pancreatic Sarcoma

Primary pancreatic sarcomas are extremely rare entities, accounting for less than 0.1% of all pancreatic neoplasms1. They originate from the mesenchymal tissue of pancreatic support, and the leiomyosarcoma subtype is the most frequently reported2. This neoplasia usually presents poor prognosis due to late diagnosis and accelerated growth relative to other pancreatic neoplasia1,3. The pancreatic head is the most commonly involved site, followed by the tail and body, and it occurs more frequently in younger individuals3. Clinically, patients may present with weight loss, palpable abdominal mass, epigastric pain, nausea and vomiting, similar to other pancreatic diseases, thus being unspecific to sarcomas1-3. On CT scanning, the findings include a bulky, heterogeneous mass and, with peripheral enhancement after contrast injection, pseudocystic masses are also described.CSV is an exclusive marker of sarcoma regardless of its tissue origin4. The prognosis is influenced by the patient’s age, tumor size, the presence of tumor necrosis, and vascular invasion. The curative treatment is surgical – extensive surgical resection should be advocated, even when morphologic results show a low-grade lesion2. The tumor is likely to metastasize to the liver but not to regional lymph nodes. The role of chemot

Primary Pancreatic Sarcoma

Primary pancreatic sarcomas are extremely rare entities, accounting for less than 0.1% of all pancreatic neoplasms1. They originate from the mesenchymal tissue of pancreatic support, and the leiomyosarcoma subtype is the most frequently reported2. This neoplasia usually presents poor prognosis due to late diagnosis and accelerated growth relative to other pancreatic neoplasia1,3. The pancreatic head is the most commonly involved site, followed by the tail and body, and it occurs more frequently in younger individuals3. Clinically, patients may present with weight loss, palpable abdominal mass, epigastric pain, nausea and vomiting, similar to other pancreatic diseases, thus being unspecific to sarcomas1-3. On CT scanning, the findings include a bulky, heterogeneous mass and, with peripheral enhancement after contrast injection, pseudocystic masses are also described. CSV is an exclusive marker of sarcoma regardless of its tissue origin4. The prognosis is influenced by the patient’s age, tumor size, the presence of tumor necrosis, and vascular invasion. The curative treatment is surgical – extensive surgical resection should be advocated, even when morphologic results show a low-grade lesion2. The tumor is likely to metastasize to the liver but not to regional lymph nodes. The role of chemo

Novel Insights of Effects of Pregabalin on Neural Mechanisms of Intracortical Disinhibition in Physiopathology of Fibromyalgia: An Explanatory, Randomized, Double-Blind Crossover Study

Background: The fibromyalgia (FM) physiopathology involves an intracortical excitability/inhibition imbalance as measured by transcranial magnetic stimulation measures (TMS). TMS measures provide an index that can help to understand how the basal neuronal plasticity state (i.e., levels of the serum neurotrophins brain-derived neurotrophic factor (BDNF) and S100-B protein) could predict the effect of therapeutic approaches on the cortical circuitries. We used an experimental paradigm to evaluate if pregabalin could be more effective than a placebo, to improve the disinhibition in the cortical circuitries in FM patients, than in healthy subjects (HS). We compared the acute intragroup effect of pregabalin with the placebo in FM patients and healthy subjects (HS) on the current silent period (CSP) and short intracortical inhibition (SICI), which were the primary outcomes. Pain scores and the pain pressure threshold (PPT) were secondary outcomes.Methods: This study included 27 women (17 FM and 10 HS), with ages ranging from 19 to 65 years. In a blinded, placebo-controlled clinical trial, participants were randomized to receive, in a cross-over manner, oral pregabalin of 150 mg or a placebo. The cortical excitability pain measures were assessed before and 90 min after receiving the medication.Results: A generalized estimating equation (GEE) model revealed that in FM, pregabalin increased the CSP by 14.34% [confidence interval (CI) 95%; 4.02 to 21.63] and the placebo reduced the CSP by 1.58% (CI 95%; −57 to 25.9) (P = 0.00). Pregabalin reduced the SICI by 8.82% (CI 95%, −26 to 46.00) and the placebo increased it by 19.56% (CI 95%; 8.10 to 59.45; P = 0.02). Pregabalin also improved the pain measures. In the treatment group, the BDNF-adjusted index was positively correlated and the serum S100-B negatively correlated with the CSP, respectively. However, in the HS, pregabalin and the placebo did not induce a statistically significant effect in either intracortical excitability or pain measures.Conclusion: These results suggest that pregabalin’s effect on cortical neural networks occurs, particularly under basal neuronal hyperexcitability, because its impact on the cortical excitability and the pain measures was observed only in the FM group. This indicates that pregabalin increased the CSP to induce inhibition in specific neural networks, while it increased the SICI to improve the excitability in other neurobiological systems. Trial registration in clinicaltrials.gov Identifier: NCT02639533

The molar tooth sign and the bat wing appearance in Joubert syndrome

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The molar tooth sign and the bat wing appearance in Joubert syndrome

A 10-year-old female patient was brought to the outpatient clinic with a history of neurodevelopmental delay, gait and limb incoordination, and oculomotor apraxia. According to her parents, the girl had always showed delayed acquisition of motor milestones when compared to other children, which became more evident when she was 8 months old and was not able to sit. She was able to sit by age of 2, and walked independently, but unsteady, when she was 3.5 years old. She presented with cognitive impairment. Reviewing her history, it became clear that she was hypotonic at birth and subsequently developed gait ataxia in early childhood. She was born to nonconsanguineous parents and there were no other similar cases in her family. On physical examination, she held her head preferentially in a lateralized position to her right side. She showed gait ataxia in tandem walking, abnormal stance with a positive Romberg’s sign, dysmetria, dysdiadochokinesia, diffuse hyperreflexia, bilateral Babinski sign, and oculomotor apraxia. The Wechsler Intelligence Scale for Children-III (WISC-III) demonstrated an IQ of 67 (intellectual disability). There were no other abnormalities on physical examination. Electroencephalogram showed focal paroxysmal discharges of moderate intensity in the posterior parietal-temporal region. Brain magnetic resonance imaging (MRI) demonstrated agenesis of the cerebellar vermis with a slit in the medial line sparing the two cerebellar hemispheres (Figure 1), lengthening and thickening of the cerebellar peduncles, associated with reduction of the anteroposterior diameter of the mesencephalon, the so-called “molar tooth sign” (MTS) (Figure 2). Morphological alterations in the posterior fossa showed a 4th ventricle with a typical “bat wing” appearance (Figure 3). These findings were highly suggestive of Joubert syndrome (JS)

Primary pancreatic sarcoma

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Imaging findings in osteogenesis imperfecta

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